A HSP90 protein is one of the most abundant chaperones within eukaryotic cells and is responsible for stabilization and activity regulation of various proteins related to cell growth differentiation and survival. The substrate protein of the HSP90 which is called the client protein contains over 50 cancer-inducing proteins. If the HSP90 activity is inhibited, the HSP90 client proteins are degraded by the proteasome.
Therefore, the HSP90 activity inhibitor can decrease the activity of various cancer-inducing proteins at the same time and thus it has attracted great attention as an anticancer agent capable of being applied to a wide variety of cancers. In particular, HSP90 has been reported to be effective treatment of cancer with resistance, because it simultaneously reduces activity of various cancer-inducing proteins.
In addition, it has been reported that HSP90 inhibitor may be used as a therapeutic agent for degenerative neurological diseases, because proteins that cause degenerative nerve diseases are also present in the HSP90 client proteins.
The HSP90 inhibitor started with the development of the natural substance geldanamycin (GA). GA has been found to lead to the decomposition of Src, the client protein via inhibition of HSP90 in 1994 and thereafter inhibitors of targeting HSP90 have been developed actively. However, GA has a strong anticancer effect, but has problems of liver toxicity, solubility and stability. To compensate it, GA derivatives such as Tanespimycin (17-AAG), alvespimycin (17-DMAG) and retaspimycin are developed, but the problem has not been solved by the structural characteristics of GA. HSP90 inhibitors of various structures have been researched at the clinical stage, but since FDA-approved drug has not yet been developed, new and strong efficacious compounds are required.